HBG2 (hemoglobin subunit gamma 2; HGNC:4832, NCBI Gene ID 3048) is a human locus mapped to chromosome band 11p15.4 that encodes G-gamma-globin polypeptide chain (146 aa; carries Glycine at residue 136). HBG2 acts in fetal hemoglobin (HbF) assembly & developmental hemoglobin switching, together with HBG1 (A-Gamma Fetal Globin Gene), HBB (Adult Beta-Globin Gene), and BCL11A (Fetal Hemoglobin Repressor Gene). Encodes the G-gamma globin chain of fetal hemoglobin (HbF), predominating at birth and co-reactivated with HBG1 in genetic therapies for sickle cell disease.
Approved Symbol
HBG2
Chromosomal Locus
11p15.4
Encoded Product
G-gamma-globin polypeptide chain (146 aa; carries Glycine at residue 136)
XmnI (-158C>T) & HPFH promoter variants elevate HbF; co-targeted with HBG1 in CRISPR/base editing for beta-hemoglobinopathies
Gene Structure & Expression
Genomic Organization & Cytogenetic Locus: 3-exon gene positioned 5 kb upstream of HBG1 within the chromosome 11p15.4 beta-globin gene cluster, sharing an identical proximal promoter architecture (including the -115 bp TGACCA BCL11A binding motif and -200 bp ZBTB7A motif) and differing in coding sequence only by glycine at position 136.
Cellular & Tissue Expression Profile: Accounts for ~70% of total gamma-globin synthesis at birth (3:1 G-gamma to A-gamma ratio) before developmental hemoglobin switching reduces total HbF to <1% of adult hemoglobin (where the residual ratio shifts to ~2:3 G-gamma to A-gamma).
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Incorporates into alpha2-gamma2 HbF tetramers that cannot participate in the hydrophobic Val6 intermolecular contacts required for deoxy-HbS tactoid polymerization, thereby increasing the delay time of erythrocyte sickling exponentially as intracellular HbF concentration rises above 20–30%.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: The common upstream polymorphism rs7482144 (-158C>T, the XmnI restriction site variant) and Greek/British HPFH promoter point mutations (-114C>T, -175T>C, -198T>C) selectively boost HBG2 transcription during erythropoietic stress and markedly ameliorate sickle cell disease and beta-thalassemia phenotypes.
Therapeutic & Clinical Pharmacology: Co-derepressed alongside HBG1 by FDA-approved CRISPR-Cas9 therapy exagamglogene autotemcel (Casgevy) and directly edited at its -115/-175/-198 promoter motifs by investigational base editors and Cas12a ribonucleoproteins to recapitulate natural HPFH.